Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma

Abstract

Background: Samarium-153 ethylenediaminetetramethylene phosphonic acid ((153)Sm-EDTMP) has been used to treat patients with high-risk osteosarcoma. The purpose of the current study was to determine the maximally tolerated dose of (153)Sm-EDTMP that permits hematopoietic recovery within 6 weeks.

Methods: Patients with recurrent or refractory osteosarcoma with bone metastases were enrolled in this study. Subjects were treated with increasing doses of (153)Sm-EDTMP, beginning with 1.0 millicuries (mCi)/kg and followed initially with 40% increment dose level escalations, using a continual reassessment method for dose escalation and de-escalation with a target dose-limiting toxicity (DLT) rate of 30%. Complete blood counts were monitored weekly, and the primary DLT was defined as failure to achieve an absolute neutrophil count >750/mm(3) and a platelet count >75,000/mm(3) within 6 weeks of treatment. In addition to assessing toxicity, dosimetry measurements were made to estimate the radiation dose delivered to target lesions.

Results: The maximally tolerated dose of (153)Sm-EDTMP was 44.8 megabecquerel (MBq)/kg (1.21 mCi/kg). DLTs were confined to hematologic toxicities, particularly delayed platelet recovery in 2 patients treated at a dose of 51.8 MBq/kg (1.4 mCi/kg). Grade 2 and 3 pulmonary toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) as reported in 2 patients (at administered activities of 44.8 MBq/kg and 51.8 MBq/kg) was attributable to progressive pulmonary disease. No other significant nonhematologic toxicities were observed.

Conclusions: Patients with osteosarcoma who have previously been heavily treated with chemotherapy can be safely administered (153)Sm-EDTMP with rapid hematologic recovery. The data from the current study support the development of a future trial to assess the efficacy of combining targeted radiotherapy with cytotoxic chemotherapy as a treatment option for patients with high-risk osteosarcoma.

FIGURE 1

The continuous reassessment model. The heavy line indicates the relation between administered activity (x axis) and probability (PROB) of toxicity (y axis) as calculated by the formula given in the text. The dotted lines indicate the 90% confidence intervals. The square indicates the dose that corresponds to the predicted toxicity rate of 30%, which was the target of the model.

FIGURE 2

Relation between administered activity and adsorbed dose. (Top) The tumor adsorbed dose was measured for several lesions in each patient and compared with the dose of samarium-153 ethylenediaminetetramethylene phosphonic acid (¹⁵³Sm-EDTMP) administered to the patient. Each data point represents an individual lesion. (Bottom) Tumor adsorbed dose compared with administered activity presented by patient. The letters A–I designate individual patients, and the activity administered to each patient is presented next to the patient’s identifying letter. Each symbol represents an individual lesion, and the small horizontal line indicates the mean tumor adsorbed dose for that patient. Gy indicates grays; MBq, megabecquerel.

FIGURE 3

Time to disease progression. A Kaplan-Meier survival curve indicating the number of days from the pretreatment evaluation until the first evaluation that demonstrated radiographic evidence of progressive disease is shown. PFS indicates progression-free survival.

FIGURE 4

Correlation between adsorbed dose and tumor response. The median and range of tumor adsorbed doses for the patients who experienced stable disease (SD) are compared with the median and range of tumor adsorbed doses for the patients who experienced progressive disease (PD). Gy indicates grays.